Preclinical efficacy of GPR4 antagonist in a short-term mouse emphysema-exacerbation model

In COPD, airway acidification is a common phenomenon associated with decreased antibacterial activity and persistent bacterial colonization. GPR4 is a proton sensing G protein-coupled receptor highly expressed on endothelial cells that induces a signaling cascade via coupling to Gs/cAMP formation and serves as an important interface between airway acidification and inflammation. Here we present the characterization of a short-term mouse model that mimics several of the pathophysiological features observed in bacterial COPD exacerbations in humans, rendering it very useful for pharmacological studies. Additionally, we report that inhibition of GPR4 by a small molecule antagonist (Miltz et al., 2017) rescues some of these manifestations. Mice received porcine pancreatic elastase (0.4U) intratracheally (i.t.) at day 0 to induce emphysema. After 10 days to allow resolution of acute inflammation, lipopolysaccharide (2mg/kg) was administrated i.t. to mimic acute bacterial exacerbation. Treatment with the GPR4 inhibitor started 1 day later (twice daily for 4 days, 100mg/kg, per os). Our emphysema-exacerbation model recapitulates many hallmarks of human COPD exacerbation within 2 weeks e.g. small airway remodeling, increased mucus production, lung permeability and edema, induced cytokines and proteases release and significant airway obstruction (FEV100ms/FVC). In this model, GPR4 inhibition significantly reduced lung permeability, immune cells influx, pro-inflammatory cytokines, detrimental mucin MUC5AC and proteases MMP9/12. To conclude, we characterized a short-term mouse model of emphysema-exacerbation with useful properties for pharmacological research; moreover, we show that GPR4 inhibition is a promising approach for reducing severity of acute COPD exacerbations.